brain

sciences
Review
Cognition, The Menstrual Cycle, and Premenstrual
Disorders: A Review
Jessica Le, Natalie Thomas and Caroline Gurvich *
Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University and The Alfred Hospital,
Melbourne, VIC 3004, Australia; jle30@student.monash.edu (J.L.); natalie.thomas@monash.edu (N.T.)
* Correspondence: caroline.gurvich@monash.edu




Received: 1 March 2020; Accepted: 26 March 2020; Published: 27 March 2020


Abstract: Sex hormones, such as estrogens, progesterone, and testosterone, have a significant influence
on brain, behavior, and cognitive functioning. The menstrual cycle has been a convenient model to
examine how subtle fluctuations of these hormones can relate to emotional and cognitive functioning.
The aim of the current paper is to provide a narrative review of studies investigating cognitive
functioning in association with the menstrual cycle in biological females, with a focus on studies that
have investigated cognitive functioning across the menstrual cycle in females with premenstrual mood
disorders, such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD).
In line with previous reviews, the current review concluded that there is a lack of consistent findings
regarding cognitive functioning across the menstrual cycle. Most studies focused on changes in
levels of blood estrogen, and neglected to explore the role of other hormones, such as progesterone,
on cognitive functioning. Cognitive research involving premenstrual disorders is in its infancy, and it
remains unclear whether any cognitive disturbances that are identified may be attributed to negative
experience of mood and psychological symptoms or be a more direct effect of hormonal dysregulation
or sensitivity. Suggestions for future research are provided.

Keywords: cognition; menstrual cycle; premenstrual mood disorders; premenstrual syndrome (PMS);
premenstrual dysphoric disorder (PMDD)

1. Introduction
Sex steroid hormones, such as estrogens, progesterone, and testosterone influence cognitive
functioning and have been at the basis of studies examining sex differences in behavior for decades.
The menstrual cycle is a model of hormonal flux that has garnered interest in understanding hormonal
influences on emotional and cognitive functioning. The influence of sex hormones on cognitive
functioning has primarily been driven by sex differences historically demonstrated in certain cognitive
tasks. More recently, menstrual cycle phase-based assessments of cognition have been applied to
clinically-relevant disorders such as premenstrual syndrome (PMS) and premenstrual dysphoric
disorder (PMDD). Both of these disorders have significant psychosocial impacts in the week(s) leading
up to menstruation, but the cognitive aspects of these disorders have not been fully explored. This paper
is a narrative review of current literature examining cognitive functioning over the menstrual cycle,
with a specific focus on determining the current understanding of cognition in PMS and PMDD.

2. The Menstrual Cycle and Premenstrual Disorders

The menstrual cycle is the physiological process in which sex hormone fluctuations alter the
uterus lining and drive ovarian production of eggs so reproduction can occur [1]. The hormonal
fluctuations of the menstrual cycle are regulated by the hypothalamus–pituitary–gonadal (HPG) axis.
The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior

Brain Sci. 2020, 10, 198; doi:10.3390/brainsci10040198 www.mdpi.com/journal/brainsci

Brain Sci. 2020, 10, 198 2 of 14

pituitary to produce luteinizing hormone (LH) and follicle stimulating hormone (FSH). Both LH and
FSH stimulate the ovaries in females to produce estrogen and progesterone. Hormone levels then
negatively feed back to the hypothalamus and pituitary to decrease GnRH, LH, and FSH secretion.
For women of reproductive age with regular cycles, cycle length is normally between 24–35 days [2].
There are two broad phases, the follicular phase and the luteal phase. The follicular phase starts on
day 1 of menses and ends with ovulation, followed by the luteal phase until menses occurs again,
when the cycle repeats. In the first week (the early follicular phase) estradiol and progesterone are
typically at low levels. In the following week, the late follicular phase, estradiol rises rapidly, and just
before ovulation, there is an LH surge. In the luteal phase, estradiol falls sharply then starts to rise
again, while progesterone rises to peak at day 21 in a 28-day cycle. Both hormone levels then gradually
fall in the late luteal phase before menses.
The psychological effects of the menstrual cycle have received increasing interest particularly
due to their clinical relevance in premenstrual disorders such as PMS and PMDD. Premenstrual
psychological changes can include emotional changes, such as irritability, mood lability, or depressed
mood, as well as cognitive symptoms such as difficulties concentrating [3]. While PMS generally refers
to any somatic or psychological symptoms that impact functioning [4], PMDD is a newly- recognised
psychiatric disorder which afflicts 1–8% of women [5,6], often conceptually placed at the extreme end of
premenstrual symptom severity. PMDD has strict diagnostic criteria which were implemented into the
American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-5) in 2013 [3]. While the
etiology remains unknown, the general consensus is that premenstrual symptoms are due to an
increased central nervous system sensitivity to menstrual cycle hormone fluctuations [7,8]. Symptoms
generally occur cyclically in the late luteal phase of the menstrual cycle, and remit once menses
occurs in the follicular phase. Possible mechanisms involved include dysregulation of progesterone’s
main metabolite, allopregnanolone, in combination with serotonergic and gamma aminobutyric acid
(GABA)ergic pathways [7,8].

3. Sex Hormones and Cognition

There is a substantial body of literature that demonstrates the influence of sex hormones
on cognitive processes. The clearest evidence of direct neurological effects of estrogen and
progesterone was the discovery of their receptors in multiple sites of the brain (aside from the
hypothalamus). Both estrogen receptors (ER-α and ER-β) and progesterone receptors (PR-A and
PR-B) have been found in cognitively-relevant brain regions, such as the amygdala, hippocampus,
and the prefrontal cortex [9,10]. Both hormones are lipophilic, which means peripheral levels
can pass through the blood–brain barrier [11]. Furthermore, they influence synaptic formation
through various signaling pathways and play critical roles in neuroprotection [9,10,12]. Rodent
studies demonstrate ovariectomized rats had decreased dendritic spine density of neurons in
the hippocampus and prefrontal cortex [13], with increased spinal density in these areas after
exogenous estradiol administration [14,15]. Such studies also demonstrated an estrogen-enhanced
correlation with performance on memory tasks [13,15]. Progesterone has been studied less extensively.
While progesterone is considered neuroprotective for cognition after traumatic brain injury [10], rodent
studies indicate it initially enhances, but then antagonizes estradiol enhancement of spinal density [16].
Estrogen and progesterone also interact with cognitively-relevant neurotransmitter systems, which
include serotonergic, GABAergic, dopaminergic, and glutamatergic pathways—all of which play roles
in executive function, learning, or memory [12].
Sex hormones have also demonstrated cognitive effects in human clinical studies. Estrogen
depletion in natural or surgical menopause is potentially associated with cognitive impairment [17],
and is a possible explanation as to why more women than men suffer, with greater severity, from
neurocognitive disorders with postmenopausal onset such as Alzheimer’s disease [18]. There is
also a large body of research investigating the effects of exogenous administration of sex hormones
on cognition. This includes hormone replacement therapy in peri-menopausal and menopausal
Brain Sci. 2020, 10, 198 3 of 14

women [19–21] and oral contraceptive pills [22], as well as the effects of induced hypogonadism and
hormone add-back therapy in young, healthy women [23,24]. This review, however, focuses on the
influence of endogenous hormones in relation to the menstrual cycle and premenstrual mood disorders.

4. The Menstrual Cycle and Cognition

The menstrual cycle has long been a convenient model to examine the influence of endogenous sex
hormones on cognitive functioning within a short time frame. Both “hot” (emotion-related) and “cold”
(emotion-independent) cognition have been explored across the menstrual cycle. Emotion-related
cognitive processes which have been studied include fear conditioning [25,26], e.g., emotional facial
recognition (see review [27]) and emotion processing (see reviews [11,28]). Evidence suggests there
are associations between emotion-dependent cognitive processes and menstrual cycle phase, with the
luteal phase associated with poorer performance on emotion-related cognition. The evidence in
relation to “cold” or emotion-independent cognition is less consistent [11,28] and is the focus of the
current review. Most research into neurocognitive performance has been conducted with a hypothesis
that stems from research into cognitive sex differences. Historically, it is claimed that men perform
better in visuospatial tasks, while women demonstrate an advantage in verbal skills [29]. This theory
was applied to the menstrual cycle by assuming that performance in these "sex dimorphic” tasks
differed, at least in part, due to levels of sex hormones [30]. The hypothesis was that women would
perform better in the follicular phase (when sex hormone levels were low) on visuospatial tasks that
historically have been described as male favoring tasks. In contrast, performance on verbal tasks that
are suggested to favor females would be improved in the luteal phase when levels of sex hormones
were higher. Of the visuospatial task, the 3D cube mental rotation task, first devised by Shepard and
Metzler [31], and adapted into a pen-and-pencil task by Vandenberg and Kuse [32], has been associated
with the most consistent findings and the largest effect size [33] in relation to the research examining
sex differences in cognition.
Studies of the menstrual cycle involve comparison of performance between at least two time
points of the menstrual cycle. Sundström-Poromma and Gingnell’s comprehensive review in 2014 [11]
of menstrual cycle studies in cognition concluded that there was insufficient evidence to support the
hypothesis that male-favoring cognitive tasks would be improved in the follicular phase. Their review
only included methodologically sound studies which conducted hormonal confirmation of menstrual
cycle phase to streamline study quality. Across the 12 studies included for mental rotation, four studies
supported the hypothesis [34–37] while the others had no significant findings [38–45]. However,
multiple studies had methodological issues: three studies [36,38,46] had small sample sizes of under
ten participants, significantly limiting their power; one study did not counterbalance the participants
to prevent practice effects on results [34]; and two studies had cross-sectional study designs testing
the participants only in one menstrual cycle phase [35,42], which can highly bias the results as
inter-individual variability in baseline hormone levels and baseline cognitive capacity cannot be
accounted for. Four of the studies compared performance between low and high estradiol [38,42,43,46],
whether between the early and late follicular phase or between arbitrary points of different levels.
This does not account for possible effects of progesterone and general menstrual phase. Four of
the studies used the earlier version of the mental rotation test devised by Shepard and Metzler,
instead of the Vandenberg–Kuse mental rotation task [34,40,41,43], which produces more pronounced
sex differences. Studies that did find phase differences in mental rotation and other visual spatial
tasks (including visual reproduction and spatial math tasks) all showed enhanced performance in
the follicular phase [34–36,47,48]. Moreover, the two functional magnetic resonance imaging (fMRI)
studies [38,45] in mental rotation showed there were brain activation differences in mental rotation
between the sexes and enhanced activation for women in high estrogen phases (pre-ovulatory and
mid-luteal) despite no significant performance differences. Estradiol concentrations were also correlated
with increased activation.
Brain Sci. 2020, 10, 198 4 of 14

For verbal skills, the studies included in the 2014 review were similarly inconclusive. The two
main cognitive domains identified in meta-analysis as favoring females are verbal fluency and verbal
memory [49]. Two of the six studies examining verbal fluency showed improved performance in
periods of high estradiol [37,50], such as the mid-luteal phase or the late follicular phase, while the
remaining studies showed no effect of phase [41,42,44,46]. Other studies of verbal skills have varied
in the tests used, ranging from paragraph recall [47], implicit and explicit verbal memory tests [37],
the California Verbal Learning Test [44], and verbal working memory [51]. No significant pattern has
emerged in results. Results were subject to similar methodological inconsistencies—small sample sizes
and two studies were cross-sectional [35,42]. The early follicular and mid-luteal phase were generally
tested as comparisons. However, one study, which failed to detect a phase effect compared the early
follicular phase and the days straight after ovulation, both phases when hormone levels are low [46],
and thus their study design was not able to measure cognition at differing hormone levels.
The 2014 review showed that much of the evidence still required greater methodological rigor, and
placed into question whether the menstrual cycle could sufficiently capture cognitive changes based
on this historical hypothesis. An fMRI study by Pletzer et al. [52] demonstrated that despite a lack of
menstrual cycle phase effect in performance on spatial navigation and verbal fluency tasks, there were
differences in brain activation patterns during the follicular and luteal phases. Specifically, there was
enhanced hippocampal activity during the pre-ovulatory, higher estradiol phase and enhanced
fronto-striatal activation during the high progesterone luteal phase; these changes were irrespective
of task. This study shows that sex hormones likely influence cognitive processes, but challenges
the concept of ‘male’ or ‘female-favoring’ cognitive tasks over the menstrual cycle. Furthermore,
contemporary research regarding sex differences in cognitive performance is moving toward a
bio-psycho-social model [53,54] which involves socio-cultural factors as well as levels of androgenic
sex hormones (e.g., testosterone). Preliminary studies also show that aside from performance, spatial
cognitive strategies in the luteal phase may be more “egocentric” than “allocentric” [55,56], which is
when spatial tasks are conducted in relation to one’s own perspective instead of cardinal direction
(e.g., those of a compass). Such findings suggest that changes in gross performance across a menstrual
cycle might not sufficiently capture the potentially subtle influence of sex hormones on cognitive
abilities and cognitive strategies.
Aside from traditionally sex dimorphic tasks, menstrual cycle studies have also considered
executive functioning tasks. Executive function is an umbrella term, referring to higher order cognitive
processes, such as the capacity to monitor, organize, think flexibly, and plan. These processes are partly
attributed to dopamine modulation within prefrontal brain regions, and sex hormone interactions with
dopaminergic pathways [57]. Studies have similarly been inconclusive, mainly due to the heterogeneity
of different tests used measuring varying aspects of executive function. The Wisconsin Card Sorting
Test, which assesses shifting of mental set (or flexible thinking) and problem solving, had mixed results
in two separate studies by the same authors. One study [58] showed better performance in the early
luteal phase, when progesterone levels are at their highest, relative to late luteal phase and ovulation
phase. The other study did not observe a menstrual cycle phase effect on this task [50]. Inhibition
and selective attention performance varied depending on the task. Performance was shown to be
impaired in the late follicular phase in a stop-signal task [59], improved in levels of high estradiol for
the Stroop task [60], and improved in the late follicular phase for inhibitory return [61]. Thimm’s fMRI
study using the Go/No-Go task showed that reaction times to the right visual field were faster in the
early follicular phase (lower levels of estradiol) compared to the late follicular phase, but imaging
did not produce clear findings to mirror the behavioral results [62]. High levels of estradiol have
also been suggested to be related to improved working memory performance in verbal and spatial
contexts [51,63].
Overall, the research is inconsistent regarding the menstrual cycle influence on cognition. In many
of these studies, levels of estrogen, as opposed to progesterone have been explored as the modulator
of cognitive performance. This is limiting, as progesterone in animal studies has an influence on
Brain Sci. 2020, 10, 198 5 of 14

cognition, with perhaps even an inhibitory effect on estrogen. Fluctuations of the menstrual cycle
may also be too transient to reveal substantial findings, or methodological issues may cloud robust
findings. Nevertheless, as Sundström-Poromma and Gingnell concluded in 2014 [11] and similarly
in 2018 [11,28], methodologically-sound studies do not appear to demonstrate significant effects of
menstrual cycle phase on cognitive performance.

5. Premenstrual Mood Disorders and Cognition

The studies of the menstrual cycle reviewed in Section 4 assessed groups of healthy women.
Comparatively, as biological females with premenstrual mood disorders have a potential vulnerability
to sex hormone fluctuations, it remains to be concluded whether changes in their cognition may
be more detectable or pronounced in these clinical disorders. Women with PMS and PMDD have
no absolute differences in peripheral hormone levels [7]. As previous menstrual cycle studies can
only compare cognitive performance between absolute high and low hormone levels, investigating
women with premenstrual mood disorders also considers the effect of sensitivity to hormone kinetics.
Clinically, women with PMS and PMDD also describe symptoms in the late luteal phase that could be
related to altered “cold” cognitive functioning, such as difficulty concentrating and impaired work
productivity [7]. Symptoms such as affective lability, and a sense of being overwhelmed or experiencing
a lack of control, could also involve alterations in cognitive-affective processes. Thus, it is imperative
to understand if an objective cognitive change accompanies these symptoms.
Studies measuring cognitive performance in these clinical groups have similar study designs to
previous menstrual cycle studies—they are repeated measure and compare cognitive performance
between the follicular and the luteal phases. For the current narrative review, we considered
observational studies evaluating cognitive performance in women with PMS or PMDD published
in English after 1960. Studies were included if they involved: (a) a study group of premenopausal
females experiencing symptoms of PMS or PMDD; (b) at least one clinical measure of cognitive
performance assessing one or more of the following domains: attention, memory, working memory,
executive function (including inhibitory control), verbal, or visuospatial abilities; and (c) the inclusion
of a separate control group of naturally-cycling women without symptoms of PMS or PMDD or the
evaluation of groups based on severity of PMS / PMDD. Exclusion criteria were (a) studies involving
administration of additional medications or study conditions with potential for cognitive impact,
unless meaningful analysis of baseline evaluations was reported, and (b) if full text of the studies
were unable to be accessed. The most recent search was conducted on 23rd March 2020. Databases
included MEDLINE, Scopus, and PubMED using the following key words “premenstrual syndrome”,
“premenstrual mood disorder*”, “PMDD” or “Premenstrual Dysphoric Disorder” AND “cognition”,
“cognitive performance”, “cognitive function”, “verbal”, “visuospatial”, “attention”, or “executive
function”. Due to the small number of studies in the area, studies were not excluded on basis of
methodological quality. While menstrual cycle studies in healthy women have primarily focused
on cognitive tasks considered sexually dimorphic, studies on PMS and PMDD have focused more
on cognitive domains such as executive functioning and attention, which are commonly affected in
psychiatric disorders and significantly impact psychosocial functioning [64]. Cognitive performance
between the subject groups and between phases was reviewed.

5.1. Studies of PMS and Cognition

Five studies have examined cognitive performance in women with PMS, as outlined in Table 1.
PMS is characterized in different ways across studies, so participant groups with PMS are likely to be
broad and heterogeneous. Three studies demonstrated significant group differences, but reported that
differences were small [65–67]. Of these studies, one study [66] included a healthy control group of
naturally-cycling women who were not experiencing any PMS symptoms and the remaining two studies
compared women with PMS by severity of symptoms instead of having an asymptomatic control
group (e.g., “severe” vs. “mild”) [65,67]. Their findings suggest that increased severity of premenstrual
Brain Sci. 2020, 10, 198 6 of 14

symptoms could be associated with poorer cognitive performance. This implies that differences could
be more pronounced in a PMDD group, who experience more clinically-significant symptoms.
Within the domain of attention, findings have been inconsistent. Attention span and working
memory were assessed using the Digit Span task in three studies. This task asks participants to
recall a string of numbers, then repeat the numbers in the same or reverse, backward order [68].
A computerized visual version of this task has been associated with slight (but statistically significant)
differences between “high-symptom” and “low symptom” PMS participants in the luteal phase [65],
with no significant differences across phases or between PMS and non-PMS groups in the two other
studies [66,69]. The Trail Making Test, A and B assesses visual attention, psychomotor speed, and the
capacity to divide attention (Trails B only). The task asks subjects to connect dots between numbers
and letters—Trails A is numbers only, and Trails B alternates between numbers and corresponding
letters [66]. Trails B, which is more complex and involves executive functioning skills such as ‘switching’
between numbers and letters, was one of few tasks to demonstrate group differences in Keenan et al.’s
study [66]. This finding suggests that higher order functioning may be more impaired than other
cognitive domains in women with PMS. However, performance in both the PMS and non-PMS groups
remained in the 75th–90th percentile for their age, and a colored variation of the Trail Making task in
Morgan et al.’s study showed no group differences [69]. Rapkin et al. used a non-specific psychomotor
speed test which measured the speed subjects could find specified digits in lines of numbers, which
also demonstrated no differences [70].

Table 1. Cognitive studies in premenstrual syndrome (PMS).

Hormone Group or Phase

Author Year Sample Size Cognitive Task
Assays Differences
10 PMS Mental arithmetic, No significant group or
Rapkin et al. [70] 1989 No
9 controls perceptual speed test phase differences
↓ performance in “high
8 ‘high symptom’ PMS,
Diener et al. [65] 1992 Digit Span, letter detection No symptom” group in luteal
8 ‘low symptom’ PMS
phase
Significant group,
non-phase-dependent
California Verbal Learning impairment in California
Test, Stroop task, Trails A Verbal Learning Test,
14 PMS
Keenan et al. [66] 1992 and B, verbal fluency, No ↓ performance in Trails B
10 controls
finger tapping, grip task in the luteal phase
strength, digit span (performance still within
standardized range for
healthy females)
Color trail-making, figure
maze test, block design,
30 PMS figure memory, verbal Urine LH No significant group or
Morgan et al. [69] 1996
31 controls paragraph recall, visual ovulation test phase differences.
memory, digit symbol test,
digit span
Hopkins verbal learning
test, letter–number ↓ performance in N-back
13 Mod/Severe PMS
Slyepchenko et al. [67] 2017 sequencing, N-back task, No task in the follicular phase of
27 Mild/no PMS
finger tapping, emotional moderate/severe PMS group.
Stroop task
“↓” means “Reduced”.

In relation to verbal memory, Keenan et al. found that women with PMS had impaired word
recall and learning of new words below normal ranges in the California Verbal Learning Test (CVLT)
that was non-phase dependent [66], but the other two studies using different tests (verbal paragraph
recall [69] and the Hopkins Verbal Learning Test [67]), with larger samples showed no significant
group differences. Slyepchenko et al.’s study [67] is the only study from the last decade, and found
that PMS participants had poorer accuracy in the N-back task, a working memory task that is also
impaired in PMDD studies reviewed below. Their study was novel by comparing groups only in the
follicular phase. Their findings suggest that cognition may be affected outside of the symptomatic
Brain Sci. 2020, 10, 198 7 of 14

period, or they could be incidental given that their study cannot control for inter-individual variability
in baseline performance.

5.2. Studies in PMDD and Cognition

Studies examining PMDD and cognitive performance are also limited, as summarized in Table 2.
As a psychiatric disorder with a severe functional impact on interpersonal relationships, work and
leisure, studies have examined if cognitive impairment exists in the luteal phase in women with this
disorder. Studies from the 1990s tended to use the rationale that PMDD was a similar entity to major
depressive disorder, and thus because cognitive deficits have been found in depression, similar deficits
may be found in PMDD. At this time, PMDD was only part of the DSM-IV as a disorder requiring
further research, and the first rank symptom was “markedly depressed mood” instead of affective
lability, the first rank symptom in the DSM-5. More recent studies have focused on including cognition
as part of a more holistic assessment of the disorder, or to identify cognitive deficits which may explain
certain symptoms. For example, Yen et al.’s two studies in 2012 and 2014 [71,72] attempted to make
links between working memory, irritability, and emotional regulation.

Table 2. Cognitive studies in premenstrual dysphoric disorder (PMDD).

Hormone Results in PMDD

Author Year Sample Size Tests Used
Assays Participants
Digit Symbol Substitution
Test, Grooved pegboard
19 PMDD ↓ psychomotor index score
test, Digit vigilance test,
Resnick et al. [73] 1998 18 mild–moderate No in the luteal phase relative to
Trail Making Test„ Stroop
symptoms follicular phase
task, California Verbal
Learning Test
10 PMDD Tower of London, spatial No significant group or
Man et al. [74] 1999 No
10 controls working memory phase differences
Word recall, digit recall, ↓ performance in all tasks
14 PMDD Each session (8
Reed et al. [75] 2008 Digit Symbol Substitution except divided attention in
15 controls times)
Test, divided attention task the luteal phase
↓ performance in the luteal
phase for all N-back tasks,
60 PMDD
Yen et al.[71] 2012 N-back task No ↓ performance in the luteal
60 controls
phase relative to follicular
phase (N3 task only)
↓ performance in the luteal
59 PMDD N-back task Once each
Yen et al. [72] 2014 phase relative to follicular
74 controls Go/No-Go phase (2 times)
phase in both tasks
Imaging studies
14 PMDD No significant group
Bannbers et al. [76] 2012 Go/No-Go No
13 controls differences
PET: 15 PMDD, Overall ↓ performance
15 controls; compared to controls (phase
Baller et al. [77] 2013 N-back task No
MRI: 14 PMDD, not studied as artificial
14 controls hormone conditions used)
“↓” means “Reduced”.

Within the domain of executive functioning and working memory, the most common task used,
with the most consistent results, was the N-back task, assessing working memory [71,72,77]. This task
involves asking participants to remember objects or letters they had seen a certain number of trials ago.
Women with PMDD had poorer performance on the task compared to the control group in the luteal
phase in all three studies, especially as the working memory demand increased. This suggests that
working memory may be impaired in women with PMDD, and that the difference in performances in
the luteal phase relative to the follicular phase becomes significant with increasing difficulty of the test.
N-back performance also negatively correlated with irritability symptoms and positively correlated
with functional impairment ratings in Yen et al.’s 2012 study [71]. This suggests that cognition may have
a direct influence on psychosocial functioning. Similarly, Baller et al. showed that atypical activation
of the dorsolateral prefrontal cortex in the N-back task in PMDD participants was positively associated
Brain Sci. 2020, 10, 198 8 of 14

with PMDD severity, earlier age of onset, and global functioning scores [77]. Furthermore, Yen et al.’s
2014 study found an association between a specific genotype of a serotonin receptor gene, HTR1A, and
impaired performance in the N2 task [72]. Although a causal relationship cannot be established, this
preliminary finding affirms a role for serotonin in PMDD and its interactions with cognition.
However, other tests of executive function have had varying results. Impaired inhibition is a
cognitive ability which could relate to impulsivity in PMDD [76]. When tested via a Go/No-Go task,
women with PMDD showed significantly poorer performance in their luteal phase relative to the
follicular phase compared to controls [72]. In contrast, Bannbers et al. found no group differences in
fMRI despite brain activation differences [76]. The Stroop task also lacked group or phase differences
in Resnick et al.’s study [73].
In the domains of attention and psychomotor speed, the Digit Span test and the Digit Symbol
Substitution Test have been used. The Digital Symbol Substitution Test examines processing speed and
attention [68]. Performance was decreased in the luteal phase for PMDD participants in Reed et al.’s
study [75], even after averaging results across four sessions in the late luteal phase and four sessions
in the follicular phase. Resnick et al. [73] found an interphase change in the PMDD participants,
but results remained within normal range for women of that age. Their results were also similar for
Trail Making Test A and B, with only small differences found. Although there was no control group,
these results may suggest that changes are subtle, and not clinically significant.
Visuospatial tasks have rarely been assessed, with only Man et al. testing spatial working
memory [74]. No differences were found between PMDD and control groups, but this was subject
to a small sample size and both groups did make more errors in the luteal phase. For verbal skills,
Reed et al. found that word recall in women with PMDD in the luteal phase was significantly
worse [75], but Resnick et al. showed no group differences using the California Verbal Learning
Test [73], even though it has shown to be impaired in PMS [66]. Tasks such as mental rotation and
verbal fluency, which have been the focus of menstrual cycle studies, have not been tested before in
PMS or PMDD. It is possible that using these tests, which may be sensitive to sex hormones, in these
disorders may identify impairments not otherwise detected by other tasks.

5.3. Limitations of Clinical Studies and Scope for Future Research

PMS and PMDD studies have yet to be as methodologically rigorous as menstrual cycle studies
in healthy women. Sample size is a clear limitation as the majority of the studies had less than
30 participants in each group. This limits the ability to extrapolate the findings to PMS or PMDD
populations. The studies, by design, are also limited to testing participants over one menstrual cycle
only. Both quantitative [78] and qualitative [79] literature describe that it is a fairly normal experience
for women’s premenstrual symptoms to change one cycle to the next, and thus the study designs do
not account for inter-cycle variability. Extending the studies however must be balanced with practice
effects in repeat cognitive testing.
Furthermore, most did not use hormonal confirmation to confirm menstrual cycle phase except
for Morgan et al. [69] who used a urine LH ovulation kit and two studies [72,75] taking serum hormone
levels at each session. Instead, only retrospective assessments of participants’ previous cycle lengths
were used to estimate when to test. This can be unreliable, and lead to assessments at inaccurate
points of the cycle. Many women also do not spontaneously ovulate every cycle, which leads to
symptom remission [80]. Serum hormone assays are standard practice for menstrual cycle studies
in healthy women [11], and they are the most direct and reliable way to assess menstrual cycle
phase and the hormone profile of individuals and subject groups [81]. Future studies should aim to
include serum hormone assessment. Timing of testing in the luteal phase also varied slightly between
studies. The main difference between studies was Yen et al.’s two studies testing participants “1 week
before menses” [71,72], which is day 21 in a standard 28-day cycle, while the other studies generally
tested between days 22 and 27 [65,66,69,73–77,82,83]. Day 21 is the peak of progesterone levels in the
menstrual cycle, whereas testing a few days later is after its withdrawal, both of which could affect
Brain Sci. 2020, 10, 198 9 of 14

symptoms and cognitive performance differently. Man et al. did not indicate when testing was done in
either phase [74]. Hormone kinetics are central to these disorders, thus timing of testing is pivotal for
interpreting the mechanisms underlying cognitive changes.
Another limitation of PMS and PMDD studies is the varied use of symptom reporting and
diagnostic tools. For a confirmed diagnosis, both PMS and PMDD require at least two cycles of
prospective daily symptom reporting [84]. It is current consensus that the Daily Rating of Severity of
Problems (DRSP) questionnaire [85] is the most widely used and validated for PMDD diagnosis [84].
None of the cognitive studies have used this questionnaire. Two studies [67,71] used a retrospective
screening tool (Premenstrual Symptom Screening Tool) which has a lower specificity than the DRSP [86],
and Diener et al. used an outdated retrospective Moos Menstrual Distress Questionnaire devised
in 1968. Therefore, these studies are subject to recall bias and inaccurately defined subject groups.
The other studies did use prospective ratings, but the lack of consistency of standardized questionnaires
used (e.g., Cyclical Diagnoser scale, “daily rating diary”) means varying subject groups may have been
captured. This varied stringency for classifying clinical groups was therefore present for control groups
too. In Slyephchenko et al.’s [67] and Man et al.’s [74] study, control subjects were acceptable as long as
they did not meet PMDD criteria, whereas Yen et al. [71,72] and Reed et al. [75] had specific criteria for
controls (e.g., having fewer than x criteria met for PMDD diagnosis). Furthermore, combining both
mild and moderate symptomatic women heterogeneously into one clinical group in Resnick et al.’s
study [73] may have masked more significant group differences. As up to 80% of women experience at
least psychological or physical symptom before menses [87], normal physiological changes must be
differentiated with clinical premenstrual disorders in order to compare the cognitive profiles of two
distinct groups.
In light of these methodological concerns, their findings are therefore only preliminary. Future
research should thus focus on developing robust study designs, as well using a broader range of
cognitive tasks. Investigating cognitive aspects of PMS and PMDD enables understanding of its
symptomology as well as clinical applications of diagnosis and management. This could also lead
to therapeutic studies exploring hormone therapies and cognitive outcomes in women with PMS
and PMDD.

6. Conclusions
The menstrual cycle is a pivotal model to study how sex hormone fluctuations can alter cognition.
Studies examining the menstrual cycle in healthy women have been unable to show consistent
associations between cognition and menstrual cycle phase. It may be that the sex difference hypothesis
behind many of these studies may be outdated, or any changes that do occur are too transient over a
monthly cycle to be detectable in gross performance changes (instead, cognitive strategies may differ
across menstrual cycle phase). Regarding premenstrual disorders such as PMS and PMDD, although
methodologically-sound studies are limited, current evidence suggests that there may be cognitive
deficits in some aspects of executive functioning in those who are most symptomatic (women with
PMDD). This suggests that while sex hormones are influencing cognitive processes over the menstrual
cycle in both healthy and premenstrual disorder groups, the effects may not be clinically relevant
until severely symptomatic. Nevertheless, it is important to consider the observational nature of these
studies means no causation of any cognitive change observed can be confirmed—it is unclear whether
the negative experience of mood and psychological symptoms affects cognitive abilities, or whether it
is an underlying hormonal dysregulation directly impacting cognition. Research into PMS and PMDD
remains in its infancy, and thus further study into these clinical disorders should be the focus. Further
study would ideally incorporate the methodological aspects of previous menstrual cycle studies,
as well as examine cognitive tasks that may be sensitive to sex hormones.

Author Contributions: Conceptualization, C.G. and N.T.; writing—original draft preparation, J.L.;
writing—review and editing, C.G. and N.T. All authors have read and agreed to the published version of
the manuscript.
Brain Sci. 2020, 10, 198 10 of 14

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.

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